Enhancing Motivated Behavior with Functionally Selective 5-HT2c Receptor Ligands. Deficits in motivation are a debilitating and pervasive symptom of several psychiatric disorders including schizophrenia and some affective disorders. Though it is widely known that serotonin influences motivation, the mechanisms involved are not fully understood. Much of what we know about the physiology of 5-HT signaling comes from in vitro pharmacological studies or in vivo experiments involving anesthetized animals. However, determining the relationship between 5-HT receptor signaling and motivated behaviors requires an in vivo approach in awake, behaving animals. The overall goal of this proposal is to begin the analysis of the specific relationships between 5-HT receptor signaling pathways and motivation. We previously identified a 5-HT2c receptor ligand (SB242084) that robustly enhances motivated behavior in wild-type mice and also in a transgenic mouse model of motivational deficit. We have determined that the enhancement in behavioral output mediated by SB242084 is specific to incentive motivation and not driven by an increase in motor activity or feeding behavior. These finding suggest that SB242084 will be a productive starting point for the analysis of the role that 5-HT receptors play in motivated behaviours. Previous studies in anesthetized rodents have demonstrated that drugs which target the 5-HT2c receptor regulate the activity of midbrain dopamine neurons and also influence the level of stimulated dopamine release in the mesolimbic dopamine pathway, an essential circuit for motivated behaviors. We therefore hypothesize that SB242084 enhances incentive motivation by altering dopamine release in the mesolimbic pathway (specifically in the nucleus accumbens) during behavior and propose to test this hypothesis directly. We will use in vivo techniques to measure the effects of systemic SB242084 treatment on the dynamics of dopamine signaling in the nucleus accumbens during behavioral tests of motivation. Because 5-HT2c receptor selective compounds can exert their influence by acting on one or more of the several potential intracellular signaling pathways that ae downstream of the receptors, in future studies we will examine which of the specific molecular signaling cascades downstream of the 5-HT2c receptor are required for the enhancement of motivation. Overall, the goal of our proposed study is to identify the mechanism of action of a psychoactive drug within an identified neuromodulatory circuit. The data we will obtain will shed new light on the role of serotonin in motivated behavios and provide critical information for the future goal of developing new compounds that will ameliorate the disruption in motivation suffered by psychiatric patients.